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Downloaded from Dbgap bioRxiv preprint doi: https://doi.org/10.1101/507939; this version posted December 28, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Sex-specific regulatory mechanisms underlying Hepatocellular 2 Carcinoma 3 4 Heini M Natri1,*, Melissa Wilson Sayres1, Kenneth Buetow1 5 6 1 Center for Evolution and Medicine, School of Life Sciences, Arizona State University, Tempe, 7 Arizona, USA 8 9 Corresponding author: 10 E-mail: [email protected] (H.M.N) 1 bioRxiv preprint doi: https://doi.org/10.1101/507939; this version posted December 28, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 11 Abstract 12 Sex differences in cancer occurrence and mortality are evident across tumor types; men exhibit 13 higher rates of incidence and often poorer responses to treatment. Targeted approaches to the 14 treatment of tumors that account for these sex differences require the characterization and 15 understanding of the fundamental biological mechanisms that differentiate them. Hepatocellular 16 Carcinoma (HCC) is the second leading cause of cancer death worldwide, with the incidence 17 rapidly rising. HCC exhibits a male-bias in occurrence and mortality. Most HCC studies, to date, 18 have failed to explore the sex-specific effects in gene regulatory functions. Here we have 19 characterized the regulatory functions underlying HCC tumors in sex-stratified and combined 20 analyses. By sex-specific analyses of differential expression of tumor and tumor adjacent 21 samples, we uncovered etiologically relevant genes, pathways and canonical networks 22 differentiating male and female HCC. While both sexes exhibited activation of pathways related 23 to apoptosis and p53 signaling, pathways involved in innate and adaptive immunity showed 24 differential activation between the sexes. Using eQTL analyses, we discovered germline 25 regulatory variants with differential effects on tumor gene expression between the sexes. We 26 discovered eQTLs overlapping HCC GWAS loci, providing regulatory mechanisms connecting 27 these loci to HCC risk. Furthermore, we discovered genes under germline regulatory control that 28 alter survival in patients with HCC, including some that exhibited differential effects on survival 29 between the sexes. Overall, our results provide new insight into the role of genetic regulation of 30 transcription in modulating sex differences in HCC occurrence and outcome and provide a 31 framework for future studies on sex-biased cancers. 32 Author Summary 33 Sex differences in cancer occurrence and mortality are evident across tumor types, and targeted 34 approaches to the treatment male and female tumors require the characterization and 2 bioRxiv preprint doi: https://doi.org/10.1101/507939; this version posted December 28, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 35 understanding of the fundamental biological mechanisms that differentiate them. Hepatocellular 36 Carcinoma (HCC) is the second leading cause of cancer death worldwide, with the incidence 37 rapidly rising. HCC exhibits a male-bias in occurrence and mortality. Here, we have characterized 38 the regulatory functions underlying male and female HCC. We show that while HCC shares 39 commonalities across the sexes, it shows demonstrable regulatory differences that could be 40 critical in terms of prevention and treatment: we detected differential activation of pathways 41 involved in innate and adaptive immunity, as well as differential genetic effects on gene 42 expression, between the sexes. Furthermore, we have detected regulatory variants overlapping 43 known HCC GWAS risk loci, providing regulatory mechanisms connecting these risk variants to 44 HCC. Finally, we discovered genes under germline regulatory control altering the overall survival 45 of patients with HCC, including some that showed differential effects between the sexes. Overall, 46 our findings create a paradigm for future studies on sex-biased cancers. 47 Introduction 48 Differences in cancer occurrence and mortality between sexes are evident across tumor types; 49 males exhibit higher rates of cancer incidence and often poorer response to treatment, including 50 some forms of chemotherapy and immunotherapy [1,2]. While differences in risk behaviors and 51 environmental exposure may explain some portion of the sex-bias, cellular and molecular 52 differences are also likely to be important. The sexes differ in their endocrinological profile, 53 immunological functions and genetic makeup [3–5]. However, sex differences are rarely 54 considered in the development of cancer therapies, and the contribution from sex chromosome 55 variation to tumor etiology remains poorly understood. Sex-biased gene expression and 56 regulatory functions may underlie differences between the sexes in disease prevalence and 57 severity [6,7]. Analyses of sex-specific regulation of gene expression are essential for 3 bioRxiv preprint doi: https://doi.org/10.1101/507939; this version posted December 28, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 58 understanding sources of sex difference in cancer incidence, as well as sex-specific mechanisms 59 affecting tumor etiology, disease progression and outcome. 60 Hepatocellular carcinoma (HCC) exhibits sex-bias in occurrence, with a male-to-female 61 incidence ratio between 1.3:1 and 5.5:1 across populations [8,9]. HCC is the second leading cause 62 of cancer mortality worldwide, accounting for 8.2% of all cancer deaths [10]. HCC risk is 63 influenced by genetic susceptibility, environmental factors such as oncogenic viral infections, 64 metabolic syndrome, and alcohol use, and shaped by numerous biological processes, resulting in 65 a high degree of genetic and transcriptional heterogeneity [11]. HCC incidence in the US has 66 doubled in the last 3 decades, attributable to increased rates of obesity [9]. 67 While sex-bias in HCC is partly attributed to sex-specific differences in risk behaviors and 68 environmental exposure, the relationship of these factors and sex as a biological variable has not 69 been systematically investigated. Previously, sex differences in HCC were explored in 70 conjunction with 12 additional Cancer Genome Atlas (TCGA) tumor types by Yuan et al [12]. 71 They discovered extensive sex-biased signatures in gene expression in HCC and other strongly 72 sex-biased cancers. 73 HCC shows evidence of molecular subtypes, though their role in sex-bias has yet to be explored. 74 More specifically, clustering analyses of gene expression data have produced a characterization 75 of four distinct HCC subtypes that differ in terms of gene expression, pathway enrichment, and 76 median survival [13]. A study utilizing a weighted co-expression network analysis method 77 discovered hub genes associated with HCC outcome [14]. On the other hand, genetic variants 78 affecting the expression of TNFRSF10 [15], PAX8 [16], and PVT1 [17] have been found to alter 79 HCC disease progression and outcome, highlighting the role of regulatory variants in HCC. How 80 these progression altering subtypes or variants are related to HCC sex-bias has not been 81 examined. 4 bioRxiv preprint doi: https://doi.org/10.1101/507939; this version posted December 28, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 82 Sex-specific analyses can reveal genetic and regulatory mechanisms of sexual dimorphism in 83 HCC susceptibility, progression, and mortality. Targeted approaches to the treatment of male and 84 female HCC will require the characterization and understanding of the fundamental biological 85 mechanisms that differentiate them. Here, we analyzed data from The Genotype-Tissue 86 Expression (GTEx) project and The Cancer Genome Atlas (TCGA) to examine the sex-specific 87 patterns of gene expression and regulation in HCC and healthy liver tissue. We find etiologically 88 meaningful differences in regulatory functions in HCC between males and females, providing 89 insight into the mechanisms underlying sex-bias in cancer. Additionally, we observed genes 90 under germline regulatory control that alter survival in sex-biased way in patients with HCC. 91 Results 92 Sex-specific patterns of gene expression HCC 93 We found sex-differences in gene expression in normal liver, tumor adjacent, and tumor tissues 94 (Fig 1). We found 13 genes showing a consistent sex-bias in expression in liver, HCC adjacent 95 tissue and HCC. Notably, we find that X-inactivation and X-linked dosage compensation appear 96 to be functioning in the healthy liver, HCC adjacent and HCC tissues. This is concluded from the 97 bulk RNAseq measurements where we observe XIST expression
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